Discussion
Dengue virus infection is endemic in tropical and subtropical regions worldwide (Figure 3) (4), and epidemics have caused major socioeconomic problems over several decades. It is estimated that dengue virus causes up to 400 million cases of illness annually, placing a particular burden on the health services in low-income countries (5, 6). The Norwegian Surveillance System for Communicable Diseases (MSIS) reported 133 cases in Norway in 2024, and over the past ten years, the annual incidence has varied between approximately 30 and 100 cases (3). The rapid spread of dengue virus is linked to climatic and demographic changes and weakened vector control over the past 30–40 years.
The virus is a member of the flavivirus family and includes four distinct human-pathogenic serotypes that are transmitted by daytime-biting mosquitoes in the Aedes family. Most infections are asymptomatic, but about one in four develop dengue fever. The condition is usually mild and self-limiting, lasting 2–7 days, and occurs 3–10 days after being bitten by an infected mosquito (7). The early phase of dengue fever can resemble other arboviral infections, as well as illnesses such as influenza and malaria. Characteristics are fever, headache, severe muscle and joint pain, retro-orbital pain, and about half of patients experience a maculopapular rash, nausea and abdominal pain. The febrile phase can be biphasic, and minor bleeding symptoms can occur.
Typical laboratory abnormalities include neutropenia, thrombocytopenia, elevated liver transaminases and hyponatremia. The disease was traditionally classified according to severity: dengue fever, dengue haemorrhagic fever and dengue shock syndrome. More recent clinical categorisation distinguishes between dengue fever and severe dengue. The course of illness can be chronologically divided into a febrile phase (lasting 2–7 days), a critical phase (24–48 hours) and a recovery phase (2–4 days). Warning signs during the critical phase, such as persistent vomiting, severe abdominal pain, facial oedema, mucosal bleeding, severe fatigue, hepatomegaly, intense thirst, pale and cold skin, and rising haematocrit, predict an increased risk of developing severe dengue virus infection (8, 9). Complications can include hepatitis, myocarditis, pancreatitis and central nervous system involvement. A case of encephalitis has previously been reported in the Journal of the Norwegian Medical Association (10). Recovery usually occurs without lasting effects, but post-infectious fatigue and depression are not uncommon. The fatality rate for dengue is below 1 %, rising to 2–5 % in severe cases and up to 20 % if left untreated (5, 8).
Infection with a specific serotype provides lifelong immunity against that serotype. Our patient's positive IgG result on the rapid qualitative test performed less than one week into the illness supported the suspicion that she had previously been infected with dengue virus, probably with a different serotype. Severe dengue rarely occurs during primary infection. The risk increases with reinfection by a different serotype. Immune complexes consisting of virus and non-neutralising antibodies against the serotype that previously infected the patient are taken up by phagocytes. This results in increased viral replication, known as antibody-dependent enhancement (7–9), and contributes to increased production of inflammatory mediators, endothelial dysfunction, coagulopathy and capillary leakage. Age, time since the previous infection, antibody concentration and serotype are also important factors in the development of severe dengue virus infection (2, 7–9). The bleeding tendency can result from factors such as thrombocytopenia due to bone marrow suppression, increased platelet destruction, apoptosis, extravasation, platelet function defects, coagulopathy and endothelial damage (11, 12).
Diagnosis of the viral infection is typically based on a combined immunochromatographic antigen and antibody test that includes IgM and IgG. The detected antigen component is a non-structural viral protein (NS1), which can be identified during the first week of illness and indicates a current or recent dengue virus infection (Figure 4). The test is easy to perform but has limitations in terms of sensitivity and specificity. Confirmatory analyses are therefore often performed using other methods. Increasing IgM and/or IgG titres in paired samples can also support diagnosis when there is clinical suspicion of disease despite negative antigen and IgM results in the initial test. The National Medical Microbiological Reference Function for diagnosing viral imported infections at Oslo University Hospital also offers supplementary serotype-specific antibody testing. PCR analysis can detect viral RNA during the febrile phase in the first week of illness. The IgM response appears 3–5 days after primary infection and later in secondary infection, while IgG typically rises within 1–3 weeks, but occurs much earlier and often more intensely in reinfections (Figure 5) (7, 13).
Atypical lymphocytes are reactive lymphocytes that can be seen in viral diseases such as mononucleosis. The cells are large, with abundant blue cytoplasm (indicating active DNA synthesis), and resemble a hybrid between lymphocytes and monocytes (Figure 1b). A marked increase in the number of plasma cells is, however, less common. Plasmacytosis is a common finding in blood smears from patients with dengue fever (14). In a prospective study, polyclonal plasma cells were found in 73 % of patients with dengue fever during the first week of illness (15). In some cases, the plasmacytosis can be so pronounced that plasma cell leukaemia must be considered as a differential diagnosis (16). Dengue fever is treated symptomatically, as no specific antiviral treatment is currently available. The World Health Organization (WHO) recommends hospital admission when warning signs appear (5, 6). Rehydration therapy is a core part of treatment, but platelet transfusion should only be considered in cases of bleeding and severe thrombocytopenia (< 20 × 109/L). Steroid treatment is not recommended for dengue shock syndrome, and there is no evidence that IVIg therapy improves the prognosis for severe dengue.
Vaccine development has been challenging, partly due to the antigenic variation between the different serotypes and the risk that cross-reactivity could trigger a more severe infection in patients without prior exposure to the virus. The vaccine available in Norway, Qdenga, is tetravalent and based on live attenuated dengue virus type 2, which is genetically modified with a capsid antigen from the other three serotypes. Experience with vaccinating tourists is limited. The Norwegian Institute of Public Health recommends that the vaccine only be offered to individuals who have had a primary infection and who are traveling to endemic areas (3). Swedish authorities allow vaccination of dengue-naive individuals for long-term travel to endemic regions, while the WHO recommends the vaccination of children in highly endemic areas (5). The immune response triggered by secondary dengue virus infection provides broad immunological protection. The risk of severe illness during a third or fourth infection is low (5), which supports the decision not to vaccinate our patient.